Evolved cytidine and adenine base editors with high precision and minimized off-target activity by a continuous directed evolution system in mammalian cells.

Continuous directed evolution of base editors (BEs) has been successful in bacteria cells, but not yet in mammalian cells. Here, we report the development of a Continuous Directed Evolution system in Mammalian cells (CDEM). CDEM enables the BE evolution in a full-length manner with Cas9 nickase. We harness CDEM to evolve the deaminases of cytosine base editor BE3 and adenine base editors, ABEmax and ABE8e. The evolved cytidine deaminase variants on BE4 architecture show not only narrowed editing windows, but also higher editing purity and low off-target activity without a trade-off in on-targeting activity. The evolved ABEmax and ABE8e variants exhibit narrowed or shifted editing windows to different extents, and lower off-target effects. The results illustrate that CDEM is a simple but powerful approach to continuously evolve BEs without size restriction in the mammalian environment, which is advantageous over continuous directed evolution system in bacteria cells.

Water temperature disturbance alters the conjugate transfer of antibiotic resistance genes via affecting ROS content and intercellular aggregation.

Spread of antibiotic resistance genes (ARGs) in aquatic ecosystems poses a significant global challenge to public health. The potential effects of water temperature perturbation induced by specific water environment changes on ARGs transmission are still unclear. The conjugate transfer of plasmid-mediated ARGs under water temperature perturbation was investigated in this study. The conjugate transfer frequency (CTF) was only 7.16 × 10-7 at a constant water temperature of 5 °C, and it reached 2.18 × 10-5 at 30 °C. Interestingly, compared to the constant 5 °C, the water temperature perturbations (cooling and warming models between 5-30 °C) significantly promoted the CTF. Intracellular reactive oxygen species was a dominant factor, which not only directly affected the CTF of ARGs, but also functioned indirectly via influencing the cell membrane permeability and cell adhesion. Compared to the constant 5 °C, water temperature perturbations significantly elevated the gene expression associated with intercellular contact, cell membrane permeability, oxidative stress responses, and energy driven force for CTF. Furthermore, based on the mathematical model predictions, the stabilization times of acquiring plasmid maintenance were shortened to 184 h and 190 h under cooling and warming model, respectively, thus the water temperature perturbations promoted the ARGs transmission in natural conditions compared with the constant low temperature conditions.

All-Inorganic CsPbBr3 Perovskite Planar-Type Memristors as Optoelectronic Synapses.

Mimicking fundamental synaptic working principles with memristors contributes an essential step toward constructing brain-inspired, high-efficiency neuromorphic systems that surpass von Neumann system computers. Here, an electroforming-free planar-type memristor based on a CsPbBr3 single crystal is proposed and exhibits excellent resistive switching (RS) behaviors including stable endurance, ultralow power consumption, and fast switching speed. Furthermore, an optically tunable RS performance is demonstrated by manipulating irradiation intensity and wavelength. Optical analysis techniques such as steady-state photoluminescence and time-resolved photoluminescence are employed to investigate the distribution of Br ions and vacancies before and after quantitative polarization, describing migration dynamic processes to elucidate the RS mechanism. Importantly, a CsPbBr3 single crystal, as the optoelectronic synapse, shows unique potential to emulate photoenhanced synaptic functions such as excitatory postsynaptic current, paired-pulse facilitation, long-term potentiation/depression, spike-timing-dependent plasticity, spike-voltage-dependent plasticity, and learning-forgetting-relearning process with ultralow per synapse event energy consumption. A classical Pavlov's dog experiment is simulated with a combination of optical and electrical stimulation. Finally, pattern recognition with simulated artificial neural networks based on our synapse reached an accuracy of 93.11%. The special strategy and superior RS characteristics of optoelectronic synapses provide a pathway toward high-performance, energy-efficient neuromorphic electronics.

Band-Edge Mixture Engineered Giant and Switchable Shift Current Generation.

Two-dimensional materials have enormous development prospects in the bulk photovoltaic effect (BPVE). The enhancement and manipulation of the BPVE are some of the key roles of its various applications. Through a simplified Hamiltonian model, this work shows that a substantial band mixture between occupied and unoccupied states could produce a large optical absorption rate with trivial topological features, resulting in a significantly enhanced shift current generation. Furthermore, this mechanism is illustrated in a realistic C3B/C3N bilayer material based on density functional theory calculation and tight-binding model. As each layer of C3B/C3N is centrosymmetric, the in-plane shift current arises from the interfacial interaction. The electron transfer between the layers gives a controllable band mixture, which offers a giant shift current reaching over ∼1500 µA/V2. In addition, we propose that interlayer sliding could reverse the in-plane shift current. Our work suggests a feasible approach for giant and switchable nonlinear optical processes.

Clinical Characteristics and Outcomes in Patients With Apical and Nonapical Hypertrophic Cardiomyopathy.

BACKGROUND: Apical hypertrophic cardiomyopathy (ApHCM) is a variant of hypertrophic cardiomyopathy, with distinct clinical characteristics and outcomes. We aimed to clarify the natural history of patients with ApHCM and identify the risk of end-stage heart failure incidence. METHODS AND RESULTS: This retrospective study was conducted on patients with hypertrophic cardiomyopathy in China between January 2009 and February 2024. Patients were stratified into ApHCM and non-ApHCM groups. The primary outcome was a composite of major adverse cardiovascular events, including all-cause deaths, heart failure hospitalization, sudden cardiac death, and ventricular tachycardia. The secondary outcome was the incidence of end-stage heart failure, defined as left ventricular ejection fraction <50%. Kaplan-Meier and univariable and multivariable Cox proportional analyses were applied. Adjustment variables were included for important baseline characteristics, comorbidities, and medication use. Of 5653 patients enrolled with hypertrophic cardiomyopathy, 584 (10.3%) had ApHCM and 5069 (89.7%) had non-ApHCM. During the median follow-up period of 4.6 years (1.6-8.0 years), major adverse cardiovascular events occurred in 32.2% (n=1808), with a lower incidence in patients with ApHCM than non-ApHCM (20.4% versus 33.3%, P<0.001). Non-ApHCM was an independent predictor of major adverse cardiovascular events (hazard ratio [HR], 1.65 [95% CI, 1.36-1.99]; P<0.001). In the serial cohort, patients with ApHCM exhibited a lower incidence of end-stage heart failure than those with non-ApHCM (12.4% versus 2.7%, P<0.001). Non-ApHCM was associated with a higher risk of end-stage heart failure development (HR, 2.31 [95% CI, 1.28-4.15]; P<0.001). In subgroup and sensitivity analysis, the results were consistent for our main and secondary outcomes. CONCLUSIONS: ApHCM is relatively common in hypertrophic cardiomyopathy and shows lower rates of all-cause mortality and heart failure hospitalizations than non-ApHCM.

Characterization of serum proteomic and inflammatory profiling at early stage of iron deficiency in weaned piglets.

The objective of this study was to examine the early serum proteomic and inflammatory profiles of weaned piglets subjected to iron deficiency. Twelve healthy piglets (Duroc × Landrace × Large Yorkshire, body weight: 4.96 ± 0.05 kg) were weaned at 21 days of age. Subsequently, these animals were randomly allocated to one of two groups, with six replicates in each group (maintaining a male-to-female ratio of 1:1), the control group (administered 100 mg/kg Fe as FeSO4·H2O) and L-Fe group (no additional Fe supplementation). The results showed that 42 days after initiating, compared with control group, routine blood analysis revealed a reduction in serum iron content, red blood cell (RBC) count, hemoglobin (HGB) content, hematocrit (HCT), and mean corpuscular volume (MCV) (P < 0.05). Subsequent sample analysis indicated a noteworthy decrease in iron deposition in the liver, spleen, and kidneys of piglets fed the L-Fe diet compared with control group (P < 0.05). However, final body weight, average daily gain (ADG), average daily feed intake (ADFI), feed conversion ratio, and tissue coefficients were similar between the two groups (P > 0.05). During the early stages of iron deficiency, piglets exhibited increased villus height (VH) and the ratio of VH to crypt depth (CD) in the duodenum (P < 0.05) and increased expression levels of iron transporters, including duodenal cytochrome (Cybrd), divalent metal transport 1 (DMT1), and ferritin light chain (FTL) (P < 0.05). Subsequently, isobaric tags for relative and absolute quantitation (iTRAQ) were used to identify serum proteins. Gene Ontology (GO) analysis of the differentially abundant proteins (DAP) revealed that 24 of the 30 DAP were involved in platelet function, immune response, cellular metabolism, transcription, and protein synthesis. Notably, prothrombin, asporin (ASPN), and Rac family small GTPase 3 (RAC3) expression was induced, whereas glycoprotein Ib platelet subunit alpha (GPIbA) expression was decreased. This was accompanied by a substantial reduction in serum complement 3 (C3) and complement 4 (C4) contents (P < 0.05), with elevated the contents of interleukin-1ß (IL-1ß), interleukin-4 (IL-4), interleukin-6 (IL-6), transforming growth factor-ß1 (TGF-ß1), and tumor necrosis factor-α (TNF-α) (P < 0.05). Our findings underscore the essential role of dietary iron supplementation in maintaining iron homeostasis and modulating inflammatory responses in piglets.

Rapid and direct detection of m6A methylation by DNAzyme-based and smartphone-assisted electrochemical biosensor.

m6A methylation detection is crucial for understanding RNA functions, revealing disease mechanisms, guiding drug development and advancing epigenetics research. Nevertheless, high-throughput sequencing and liquid chromatography-based traditional methods still face challenges to rapid and direct detection of m6A methylation. Here we report a DNAzyme-based and smartphone-assisted electrochemical biosensor for rapid detection of m6A. We initially identified m6A methylation-sensitive DNAzyme mutants through site mutation screening. These mutants were then combined with tetrahedral DNA to modify the electrodes, creating a 3D sensing interface. The detection of m6A was accomplished by using DNAzyme to capture and cleave the m6A sequence. The electrochemical biosensor detected the m6A sequence at nanomolar concentrations with a low detection limit of 0.69 nM and a wide detection range from 10 to 104 nM within 60 min. As a proof of concept, the 3'-UTR sequence of rice was selected as the m6A analyte. Combined with a smartphone, our biosensor shows good specificity, sensitivity, and easy-to-perform features, which indicates great prospects in the field of RNA modification detection and epigenetic analysis.

Suppression of ZEB1 by Ethyl caffeate attenuates renal fibrosis via switching glycolytic reprogramming.

Renal fibrosis (RF) is a common endpoint of various chronic kidney diseases, leading to functional impairment and ultimately progressing to end-stage renal failure. Glycolytic reprogramming plays a critical role in the pathogenesis of fibrosis, which maybe a potential therapeutic target for treating renal fibrosis. Here, we revealed the novel role of ZEB1 in renal fibrosis, and whether targeting ZEB1 is the underlying mechanism for the anti-fibrotic effects of ethyl caffeate (EC) to regulate the glycolytic process. Treatment of EC attenuated the renal fibrosis and inhibited ZEB1 expression in vivo and in vitro, reducing the upregulated expression of glycolytic enzymes (HK2, PKM2, PFKP) and key metabolites (lactic acid, pyruvate). ZEB1 overexpression promoted the renal fibrosis and glycolysis, whereas knockout of ZEB1 apparently attenuated renal fibrosis in vivo and in vitro. EC interacted with ZEB1 to modulate the glycolytic enzymes for suppressing the elevated glycolytic reprogramming during renal fibrosis. In summary, our study reveals that ZEB1 plays an important role in regulating glycolytic reprogramming during the renal tubular epithelial cell fibrosis, suggesting inhibition of ZEB1 may be a potential strategy for treating renal fibrosis. Additionally, EC is a potential new drug candidate for the treatment of renal fibrosis and CKD.

Correlation between insulin-like growth factor and complexity of glucose time series index in patients with newly diagnosed acromegaly: a PILOT study.

BACKGROUND: Acromegaly has a high risk of abnormal glucose metabolism. The complexity of the glucose time series index (CGI) is calculated from refined composite multi-scale entropy analysis of the continuous glucose monitoring (CGM) data. CGI is a new indicator of glucose imbalance based on ambulatory glucose monitoring technology, which allows for earlier response to glucose metabolism imbalance and correlates with patient prognosis. OBJECTIVE: To compare the differences in glucose metabolic profile and CGI between acromegaly with normal glucose tolerance (NGT) and healthy subjects. METHODS: Eight newly diagnosed patients with acromegaly (GH group) and eight age- and gender-matched healthy subjects (Control group) were included in this study. All participants underwent oral glucose tolerance test (OGTT) and 72-h CGM. A refined composite multi-scale entropy analysis was performed on the CGM data to calculate the CGI and we compare the differences in glycemic profiles and CGI between the two groups. RESULTS: After OGTT, compared with the control group, patients in the GH group had higher 2 h blood glucose (BG) (mmol/L) [GH vs control, 6.7 (6.1, 7.0) vs 5.2 (3.8, 6.3), P = 0.012], 3 h BG [5.1 (3.8, 6.5) vs 4.0 (3.4, 4.2), P = 0.046], mean BG [6.3 (6.1, 6.5) vs 5.5 (5.1, 5.9), P = 0.002], 2 h insulin (mU/L) [112.9 (46.8, 175.5) vs 34.1 (17.1, 55.6), P = 0.009], and 3 h insulin [26.8 (17.1, 55.4) vs 10.4 (4.2, 17.8), P = 0.016]. CGI was lower in the GH group [2.77 (1.92, 3.15) vs 4.2 (3.3, 4.8), P = 0.008]. Spearman's correlation analysis showed insulin-like growth factor (IGF) (r = -0.897, P < 0.001) and mean glucose (r = -0.717, P = 0.003) were significantly negatively correlated with CGI. Multiple linear stepwise regression showed that IGF-1 (r = -0.652, P = 0.028) was independent factor associated with CGI in acromegaly. CONCLUSION: IGF-1 was significantly associated with CGI, and CGI may serve as a novel marker to evaluate glucose homeostasis in acromegaly with normal glucose tolerance.

Collinear Spin Current Induced by Artificial Modulation of Interfacial Symmetry.

Current induced spin-orbit torque (SOT) manipulation of magnetization is pivotal in spintronic devices. However, its application for perpendicular magnetic anisotropy magnets, crucial for high-density storage and memory devices, remains nondeterministic and inefficient. Here, a highly efficient approach is demonstrated to generate collinear spin currents by artificial modulation of interfacial symmetry, achieving 100% current-induced field-free SOT switching in CoFeB multilayers with perpendicular magnetization on stepped Al2O3 substrates. This field-free switching is primarily driven by the out-of-plane anti-damping SOT generated by the planar spin Hall effect (PSHE), resulting from reduced interface symmetry due to orientation-determined steps. Microscopic theoretical analysis confirms the presence and significance of PSHE in this process. Notably, this method for generating out-of-plane spin polarization along the collinear direction of the spin-current with artificial modulation of interfacial symmetry, overcomes inherent material symmetry constraints. These findings provide a promising avenue for universal control of spin-orbit torque, addressing challenges associated with low crystal symmetry and highlighting its great potential to advance the development of energy-efficient spintronic devices technology.

New insights into the magnetism and magnetic structure of LuCrO3 perovskite.

A polycrystalline sample LuCrO3 has been characterized by neutron powder diffraction (NPD) and magnetization measurements. Its crystal structure has been Rietveld refined from NPD data in space group Pnma; this perovskite contains strongly tilted CrO6 octahedra with extremely bent Cr-O-Cr superexchange angles of ∼142°. The NPD data show that below Néel temperature (TN ≃ 131 K), the magnetic structure can be defined as an A-type antiferromagnetic arrangement of Cr3+ magnetic moments, aligned along the b axis, with a canting along the c axis. A noticeable magnetostrictive effect is observed in the unit-cell parameters and volume upon cooling down across TN. The AC magnetic susceptibility indicates the onset of magnetic ordering below 112.6 K; the magnetization isotherms below TN show a nonlinear behaviour that is associated with the described canting of the Cr3+ magnetic moments. From the Curie-Weiss law, the effective moment of the Cr3+ sublattice is found to be µeff = 3.55 µB (calculated 3.7 µB) while the ΘCW parameter yields a value of -155 K, indicating antiferromagnetic interactions. There is a conspicuous increase of TN upon the application of external pressure, which must be due to shortening of the Cr-O bond length under compression that increases the orbital overlap integral.

Total organic carbon content estimation for mixed shale using Xgboost method and implication for shale oil exploration.

In this study, the Xgboost method is employed for TOC estimation in mixed carbonate and siliciclastic shale from the Hashan area, Junggar Basin. The results show that this approach is effective for TOC estimation in this area although the model performance is not very excellent with a correlation coefficient of 0.54 between measured TOC and predicted TOC values, likely due to a small samples dataset. Therefore, the PCA method is applied to debase dimension of well log data from five dimensional to two-dimensional data, which enhances the correlation coefficient between the predicted and measured TOC from 0.54 to 0.68. Based on the model, the isopleth maps of TOC distributions in Fengcheng Formation were redrawn showing two shale oil exploration targets, which likely correspond to two depositional centers of this strata. All the same, the model in this work provides reliable data for shale oil evaluation in the study area and a good example under similar geological setting.

CCDC181 is required for sperm flagellum biogenesis and male fertility in mice.

The structural integrity of the sperm flagellum is essential for proper sperm function. Flagellar defects can result in male infertility, yet the precise mechanisms underlying this relationship are not fully understood. CCDC181, a coiled-coil domain-containing protein, is known to localize on sperm flagella and at the basal regions of motile cilia. Despite this knowledge, the specific functions of CCDC181 in flagellum biogenesis remain unclear. In this study, Ccdc181 knockout mice were generated. The absence of CCDC181 led to defective sperm head shaping and flagellum formation. Furthermore, the Ccdc181 knockout mice exhibited extremely low sperm counts, grossly aberrant sperm morphologies, markedly diminished sperm motility, and typical multiple morphological abnormalities of the flagella (MMAF). Additionally, an interaction between CCDC181 and the MMAF-related protein LRRC46 was identified, with CCDC181 regulating the localization of LRRC46 within sperm flagella. These findings suggest that CCDC181 plays a crucial role in both manchette formation and sperm flagellum biogenesis.

Homozygous CCDC146 mutation causes oligoasthenoteratozoospermia in humans and mice.

Infertility represents a significant health concern, with sperm quantity and quality being crucial determinants of male fertility. Oligoasthenoteratozoospermia (OAT) is characterized by reduced sperm motility, lower sperm concentration, and morphological abnormalities in sperm heads and flagella. Although variants in several genes have been implicated in OAT, its genetic etiologies and pathogenetic mechanisms remain inadequately understood. In this study, we identified a homozygous nonsense mutation (c.916C>T, p.Arg306*) in the coiled-coil domain containing 146 ( CCDC146) gene in an infertile male patient with OAT. This mutation resulted in the production of a truncated CCDC146 protein (amino acids 1-305), retaining only two out of five coiled-coil domains. To validate the pathogenicity of the CCDC146 mutation, we generated a mouse model ( Ccdc146 mut/mut ) with a similar mutation to that of the patient. Consistently, the Ccdc146 mut/mut mice exhibited infertility, characterized by significantly reduced sperm counts, diminished motility, and multiple defects in sperm heads and flagella. Furthermore, the levels of axonemal proteins, including DNAH17, DNAH1, and SPAG6, were significantly reduced in the sperm of Ccdc146 mut/mut mice. Additionally, both human and mouse CCDC146 interacted with intraflagellar transport protein 20 (IFT20), but this interaction was lost in the mutated versions, leading to the degradation of IFT20. This study identified a novel deleterious homozygous nonsense mutation in CCDC146 that causes male infertility, potentially by disrupting axonemal protein transportation. These findings offer valuable insights for genetic counseling and understanding the mechanisms underlying CCDC146 mutant-associated infertility in human males.

Vedolizumab for second-line treatment of steroid-refractory gastrointestinal late acute graft-versus-host disease.

Background: Late acute graft-versus-host disease (aGVHD) is a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with little data regarding treatment and outcomes. There is no standard treatment for gastrointestinal (GI) late aGVHD, especially for steroid-refractory (SR) GI late aGVHD. Vedolizumab, a monoclonal antibody inhibiting the migration of both naive and activated lymphocytes into the GI endothelium, has been verified to be effective for SR GI aGVHD. Methods: We retrospectively analyzed the clinical efficacy and safety of vedolizumab as the second line for SR GI late aGVHD in seven patients after allo-HSCT. Results: Four patients received two doses of vedolizumab infusion, while three patients received only one dose of vedolizumab infusion. The complete response and partial response rates were 57.1% (4/7) and 42.9% (3/7), respectively. No patient progressed to chronic GVHD during the period of follow-up. There was no severe adverse event related to vedolizumab. Conclusion: Our data suggest that vedolizumab is expected to ameliorate SR GI late aGVHD. Further data on the treatment timing, efficacy, and safety of vedolizumab are warranted in prospective clinical trials.

Effect of fatigue on quality of life in patients with rheumatoid arthritis: the chain mediating role of resilience and self-efficacy.

OBJECTIVES: Exploring the effect of resilience and self-efficacy in mediating the chain between fatigue and quality of life(QOL) in patients with rheumatoid arthritis (RA). METHODS: From June 2022 to November 2022, 423 RA patients were chosen by a convenience sample method from two tertiary care facilities in Chengdu, Sichuan Province. General Information Questionnaire, Bristol Multidimensional Scale of Fatigue in Patients with Rheumatoid Arthritis, SF-12 Health Survey Short Form, Chinese version of the ten-item psychological Resilience Scale, and Chinese-language Arthritis Self-Efficacy Scale, an 8-element version, were among the questionnaires used. RESULTS: In the physical component summary( PCS), self-efficacy, psychological resilience, and self-efficacy were all significantly mediated by fatigue (total effect mediated 8.88%). In the mental component summary (MCS), fatigue (total effect mediated 10.79%), self-efficacy (total effect mediated 8.99%), psychological resilience, and self-efficacy (total effect mediated 2.01%) were all significantly mediated by fatigue. CONCLUSION: Fatigue in RA patients can affect the quality of life both directly and indirectly through the mediating effects of psychological resilience, self-efficacy, and the chain mediating effect of psychological resilience-self-efficacy.

Solution mediated halide exchange engineering for the fabrication of a thick CsPbCl3 film and its application in photovoltaics with outstanding performance.

It is a big challenge to prepare thick CsPbCl3 films using traditional solution processed approaches owing to the low solubility of precursors of PbCl2 and CsCl in common solvents. Here, we propose an indirect solution process to prepare thick CsPbCl3 films. In this new approach, a mother film of CsPbBr3 is first prepared through a solution process, and then it is dipped into a diluted HCl/methanol solution. During the dipping process, it triggers a halide exchange reaction between Br- and Cl-, and it eventually produces a thick CsPbCl3 film (∼400 nm) with high quality and purity. Afterwards, a carbon based hole transportation layer (HTL) free solar cell with a configuration of FTO/TiO2/CsPbCl3/carbon is constructed, and it delivers an average PCE of 1.23% and an outstanding PCE of 1.39% in a batch of PSCs. Meanwhile, the solar cell maintains its 82% initial PCE after storage in open air for 31 days. This work overcomes the obstacle of the traditional solution approach for the preparation of CsPbCl3 films, which makes it promising for preparing various CsPbCl3 film-based devices via a solution process.

Microbial succession in different years of pit mud from a distillery in Sichuan for Nong-xiang Baijiu fermentation.

Microbial community and succession of 5-, 20-, and 50-year pit mud (PM) were uncovered in this study. The results showed that Bacteroidetes, Firmicutes and Ascomycota were dominant phyla in these PM samples. Interestingly, most sequences could not be classified into fungal taxa at the genus level by UNITE Database, the diversity and richness of bacteria in these PMs were higher than that of fungi. It was noteworthy that both 20-year and 50-year PMs exhibited higher abundances of Caproiciproducens and Petrimonas when compared with 5-year PM. While higher proportions of Lactobacillus and Acinetobacter were observed in the 5-year PM. Furfermore, these PMs microbiota mainly involved biosynthesis, degradation, and generation of precursor metabolites, which contributed to carbon cycling of Nong-xiang Baijiu anaerobic fermentation. Taken together, lactic acid bacteria depletion and caproic acid bacteria accumulation might be an important succession trend of PM microbiota during the long-term fermentation of Chinese Nong-xiang Baijiu. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-024-01558-4.

Targeting SRSF10 might inhibit M2 macrophage polarization and potentiate anti-PD-1 therapy in hepatocellular carcinoma.

BACKGROUND: The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma (HCC) remains poor. Although serine- and arginine-rich splicing factor (SRSF) family members play crucial roles in tumors, their impact on tumor immunology remains unclear. This study aimed to elucidate the role of SRSF10 in HCC immunotherapy. METHODS: To identify the key genes associated with immunotherapy resistance, we conducted single-nuclear RNA sequencing, multiplex immunofluorescence, and The Cancer Genome Atlas and Gene Expression Omnibus database analyses. We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems, flow cytometry, various tumor-bearing mouse models, and patient-derived organotypic tumor spheroids. RESULTS: SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8+ T cell activity. Mechanistically, SRSF10 interacted with the 3'-untranslated region of MYB, enhancing MYB RNA stability, and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1 (GLUT1), hexokinase 1 (HK1), lactate dehydrogenase A (LDHA), resulting in elevated intracellular and extracellular lactate levels. Lactate accumulation induced histone lactylation, which further upregulated SRSF10 expression. Additionally, lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages, thereby activating transcription and enhancing pro-tumor macrophage activity. M2 macrophages, in turn, inhibited the enrichment of CD8+ T cells and the proportion of interferon-γ+CD8+ T cells in the tumor microenvironment (TME), thus creating an immunosuppressive TME. Clinically, SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1 (PD-1) monoclonal antibodies (mAbs) in both murine and human preclinical models. CONCLUSIONS: The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance. Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.

Boosting the Stability of Subnanometer Pt Catalysts by the Presence of Framework Indium(III) Sites in Zeolite.

Subnanometer metal clusters show advantages over conventional metal nanoparticles in numerous catalytic reactions owing to their high percentage of exposed surface sites, abundance of under-coordinated metal sites and unique electronic structures. However, the applications of subnanometer metal clusters in high-temperature catalytic reactions (>600 °C) are still hindered, because of their low stability under harsh reaction conditions. In this work, we have developed a zeolite-confined bimetallic PtIn catalyst with exceptionally high stability against sintering. A combination of experimental and theoretical studies shows that the isolated framework In(III) species serve as the anchoring sites for Pt species, precluding the migration and sintering of Pt species in the oxidative atmosphere at ≥650 °C. The catalyst comprising subnanometer PtIn clusters exhibits long-term stability of >1000 h during a cyclic reaction-regeneration test for ethane dehydrogenation reaction.